This invention relates generally to nuclear magnetic resonance (NMR) and to magnetic resonance imaging (MRI), and more particularly the invention relates to the use of MR in tracking magnetically labeled cells or objects using positive contrast.
Contrast agents incorporating super-paramagnetic iron-oxide (SPIO) nanoparticles have shown much promise as a means to visualize labeled cells using MRI. The small size of the particles (<100 nm) facilitates transport across cell membranes, and the low toxicity allows for large iron loads without significant cell death (e.g., 25 pg/cell). Labeling can be performed by incubating cells of interest (e.g., embryonic stem cells) with the contrast agent in vitro, so that they can be monitored in vivo using MRI. Cells such as macrophages can be labeled in vivo by introducing the contrast agent into the bloodstream, with the uptake of the agent occurring by phagocytosis, which has been used to image atherosclerosis and other inflammatory processes. In more advanced schemes, SPIO-protein complexes that bind to the receptors on specific cells have been used.
Cells loaded with SPIO cause significant signal dephasing due to the magnetic field inhomogeneity induced in water molecules near the cell. These manifest as signal voids in the image. With the signal void as the means for detection, the particles are behaving as a negative contrast agent, as opposed to positive contrast agents such as gadolinium chelates that brighten the local signal intensity by shortening T1. A fundamental drawback of negative contrast agents is that the agent cannot be distinguished from a void in the image. Moreover, negative contrast agents suffer from partial-volume effects, where the ability to detect a void depends critically on the resolution of the image; voxel size must be smaller than the void volume for reliable visualization. While it is possible to achieve positive contrast with SPIOs by employing T1 weighting, this is only possible with the smaller-sized particles (10-50 nm) and can be inefficient because of competing T1 and T2* effects.
Co-pending application Ser. No. 10/849,068, supra, discloses a new method for imaging objects and materials that cause a localized magnetic field inhomogeneity in an MRI scanner with positive contrast. In one embodiment of the method, spectrally-selective RF pulses are used to excite and refocus the off-resonance water surrounding the cells labeled with SPIO agents, while suppressing on-resonance signal, so that only the fluid and tissue immediately adjacent to the labeled cells are visible in the image.
The present invention provides an enhancement to the off-resonance method which alleviates problems associated with background signal noise.